Septic infections kill more than 215,000 Americans each year. It is estimated that 750,000 Americans are infected with severe sepsis and 29% of them die from it each year. Sepsis deaths comprise 9% of all death cases in the U.S. Sepsis kills as many Americans as myocardial infarctions, even more than traffic accidents.
Two to three million Americans acquire a hospital infection each year and 10% of these infections progress to sepsis. More than 90,000 of these patients die from sepsis infected in hospitals.
Escherichia coli and Klebsiella pneumoniae, both Gram-negative bacteria, cause almost 40% of all community-acquired septic infections and approximately one-third of all healthcare-associated septic infections. Out of all Gram-negative septic infections, they cause approximately 60-75%. Other Gram-negative causative agents of septic infections include Acinetobacter baumannii and Pseudomonas aeruginosa. Altogether, Gram-negative bacteria cause more than 40% of all septic infections, and many of these bacteria are extremely multiresistant.
Polymyxins are a group of closely related antibiotic substances produced by strains of Paenibacillus polymyxa and related organisms. These cationic drugs are relatively simple peptides with molecular weights of about 1000. Polymyxins, such as polymyxin B, are decapeptide antibiotics, i.e. they are made of ten (10) aminoacyl residues. They are bactericidal and especially effective against Gram-negative bacteria such as E. coli and other species of Enterobacteriaceae, Pseudomonas, A. baumannii, and others. However, polymyxins have severe adverse effects, including nephrotoxicity and neurotoxicity. These drugs thus have limited use as therapeutic agents because of high systemic toxicity.
The pandemic of extremely multiresistant Gram-negative bacteria has now forced clinicians to reinstate polymyxins as the last-line therapy of severe infections, even though polymyxins are notoriously nephrotoxic. The nephrotoxicity of polymyxins may complicate the therapy or may even require its discontinuation. Accordingly, the risk of nephrotoxicity must be weighed against the beneficial effects on patient survival. According to recent studies, the nephrotoxicity rate of polymyxin B and colistin (liberated from colistin methanesulphonate) varies from 10% to 30%, but in selected materials the rate for colistin may be as high as 43 to 48% and that for polymyxin B as high as 55%. Accordingly, individual variation is high (Vaara, M. 2013, New derivatives of polymyxins, Journal of Antimicrobial Chemotherapy 2013, 68: 1213-9). The situation is made even more unfortunate by contemporary data indicating that in critically ill patients the current dosage regimens are suboptimal and lead to too low serum concentrations. Clinicians are thus advised to use larger doses, but this further increases nephrotoxicity.